The IL-12 family is comprised of three types of heterodimeric cytokines, IL-12, IL-23 and IL-27. Prior to the discovery of IL-23 and IL-27, IL-12 was thought to be the cause of several chronic inflammatory diseases because of its unique ability to induce differentiation of naive T-cells towards IFN?-secreting Th1 phenotype. However, IL-23 promotes differentiation and/or maintenance of the highly pathogenic ThIL-17 subtype and is now thought to be the primary etiologic agent in several chronic inflammatory diseases. IL-27 promotes the differentiation of naive T cells into Th1 cells but its role in host defense and immune-mediated diseases is largely unknown. Discovery of antagonism between these cytokines have led to increased interest in the roles played by these cytokines in the etiology and treatment of several chronic inflammatory diseases including uveitis. Recent reports have implicated ThIL17 cells in the pathogenesis of a number of immune-mediated diseases including experimental allergic encephalomyelitis (EAE), collagen-induced arthritis (CIA) and colitis. However, most of these studies have been in inbred mouse strain and involvement of ThIL17 cells in human diseases has not been firmly established. In this study, we examined whether ThIL17 cells are involved in two human ocular inflammatory diseases (uveitis and scleritis) and have also investigated the role of this T-cell subtype in the mouse model of human uveitis, experimental uveitis model (EAU). Uveitis is a T-cell mediated intraocular inflammatory disease of presumed autoimmune etiology. Although inhibiting the formation of high affinity IL-2 receptor (IL-2R) by a humanized anti-Tac antibody (Daclizumab) is effective therapy in treatment of these potentially binding ocular diseases, pathogenic T-cell subtypes that cause uveitis or mechanism of IL-2R action remain known. We show that a major difference between mice and "men" in this study is that ThIL17 cells are detected in normal peripheral blood mononuclear cells (PBMC) of humans but not mice. However, IL-17 is elevated in uveitis, scleritis and EAU and we show that its induction of TNFa expression in retinal cells may contribute to the pathology of chronic inflammatory disease of the eye. We further show that IL-27 is constitutively expressed in retinal ganglion and photoreceptor cells, is upregulated by IFNg and inhibits proliferation of ThIL-17-cells. These findings suggest a novel mechanism by which Th1-cells may mitigate uveitis by antagonizing ThIL17-phenotype through IFN?-mediated induction of IL-27 in target tissue. This study showing that IL-2 promotes ThIL17-cells expansion provides explanations for efficacy of anti-IL2R therapy in uveitis and suggests that antagonism of ThIL17-cells by IFNg/IL-27 maybe exploited in treating chronic inflammation.